Compound preparation for dizziness

ABSTRACT

The use of cinnarizine and dimenhydrinate or their physiologically compatible salts in combination is described for the treatment of vertigo of any genesis.

The present invention concerns the use of cinnarizine and dimenhydrinateor their physiologically compatible salts in combination.

Every tenth patient in general practice complains of vertigo. More thantwo million people annually visit their family physician due todisturbances in equilibrium. After headache, vertigo is thus the secondmost frequent symptom of disease.

Vertigo is frequently described by the patient as if he is experiencingrotational, swinging or lifting movements or the floor underfoot isunsteady. Others describe vertigo as a transitory loss of consciousnesswith confusion and insecurity of gait.

Three sensory systems are responsible for a person's orientation inspace:

the optical system,

the vestibular system and

the proprioceptive system.

Vertigo is triggered by conflicting information from these three sensorysystems due to lesions in peripheral or central equilibrium structuresor due to ocular or psychogenic disturbances. Vertigo can also be anearly sign of a serious disorder. Causes of vertigo can be vasculardisorders, cardiac-circulatory disorders, metabolic disorders anddisturbances in rheology. An interdisciplinary diagnosis is necessarydue to this plurality of possible causes.

The classification of different forms of vestibular vertigo is usuallyconducted according to the site of emergence. One distinguishes betweenperipheral-vestibular, central-vestibular and combinedcentral/peripheral-vestibular vertigo.

Information relating to the lesion site can be obtained from the mannerin which the complaints of vertigo are manifested.

The differential diagnosis of vertigo is particularly supported by acomprehensive anamnesis. The anamnesis should contain questions relatingto the type of vertigo, accompanying autonomic disturbances,vertigo-triggering situations or mechanisms, duration of attacks ofvertigo and basic or accompanying disorders. A standardized anamnesisquestionnaire, in which the course of the disease may also bedocumented, can be very helpful.

Tests for examining the vestibulo-oculary system are based on the factthat the equilibrium system responds to a labyrinth stimulus with reflexeye movements (nystagmus). Eye movements can be observed in patientsdirectly by means of Frenzel glasses or recorded with the help ofelectronystagmography (ENG) or video-oculography (VOG). Parameters thatcan be evaluated include the number of nystagmus events per unit of time(nystagmus frequency), the velocity of the slow phase of nystagmus (GLP,also: slow phase velocity, SPV) as well as the nystagmus amplitude.Standard methods for stimulating the labyrinth include caloric testingwith water or air, by means of which each labyrinth can be stimulatedand examined individually, and the rotating chair test.

If nystagmus occurs even without stimulus (thus a so-called spontaneousnystagmus is present), diagnostic conclusions can be drawn from thedirection of the nystagmus events.

For investigation of the vestibulo-spinal system, the Romberg standingtest and the Unterberger step test are particularly suitable. Thereactions of the patient can be observed directly and can be recorded bymeans of posturography or craniocorpography.

Different therapeutic approaches can lead to success, each timedepending on the cause of the vertigo.

For medicinal therapy of vertigo, there are available, among others,antihistamines, parasympatholytics, cerebrally acting calciumantagonists, benzodiazepines, neuroleptics, medications that promoteblood perfusion as well as homeopathics.

The selection of the optimal medicinal therapy is aligned with the causeof the vertigo.

The object of the present invention is thus to make available atherapeutic system which can provide therapy for all types of vertigo,i.e., vertigo of any genesis.

The object is solved by the use of cinnarizine and dimenhydrinate incombination.

One subject of the present invention is thus the use of cinnarizine anddimenhydrinate or their physiologically compatible salts in combinationfor the treatment of vertigo of any genesis.

Another subject of the present invention is the use of cinnarizine anddimenhydrinate or their physiologically compatible salts in combinationfor the preparation of drugs for the treatment of vertigo of anygenesis.

The subject of the present invention is also the use of cinnarizine anddimenhydrinate or their physiologically compatible salts in combinationalong with pharmaceutically compatible adjuvants and/or additives forthe preparation of drugs for the treatment of vertigo of any genesis.

The invention thus solves the problem of successfully treating all formsof vertigo—particularly the very frequently occurring forms of vertigothat cannot be clearly diagnosed—without erroneous therapeutical tests.Only a single medication is necessary due to the use according to theinvention of the combination of cinnarizine and dimenhydrinate as activeingredients. This represents great progress in the therapy of vertigo.

The individual active ingredients that are used in combination accordingto the invention are known in and of themselves.

Cinnarizine (CAS 298-57-7) is the international nonproprietary name(INN) for 1-benzhydryl-4-trans-cinnamylpiperazine, [which] is anantihistamine and vasodilator and is described, for example, in U.S.Pat. No. 2,882,271.

Dimenhydrinate (CAS 523-87-5) is the international nonproprietary name(INN) for the 8-chlorotheophylline salt of diphenhydramine and is anantihistamine used as an antiemetic and against travel sickness, and isdescribed, for example, in U.S. Pat. No. 2,499,058 or U.S. Pat. No.2,534,813.

These active ingredients can be utilized according to the invention alsoin the form of their physiologically compatible salts. Commonphysiologically compatible inorganic and organic acids are, for example,hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid,oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid,malic acid, citric acid, salicylic acid, adipic acid and benzoic acid.Other suitable acids, however, also include theophylline and itsderivatives, such as, for example, 8-chlorotheophylline or otherxanthines or caffeine and its derivatives. Other acids that can be usedare described, for example, in Fortschritte der Arzneimittelforschung,Vol. 10, pages 224-225, Birkhäuser Publishers, Basel and Stuttgart,1966, and Journal of Pharmaceutical Sciences, Vol. 66, pages 1-5 (1977).

The acid addition salts are usually obtained in a way known in and ofitself by mixing the free base or its solutions with the correspondingacid or its solutions in an organic solvent, for example, a loweralcohol such as methanol, ethanol, n-propanol or isopropanol or a lowerketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone oran ether such as diethyl ether, tetrahydrofuran or dioxane. Mixtures ofthe named solvents can also be used for better separation of crystals.In addition, physiologically compatible aqueous solutions of acidaddition salts of the active ingredients used according to the inventioncan be prepared from an aqueous acid solution.

The acid addition salts of the active ingredients used according to theinvention can be converted into the free bases in a way known in and ofitself, e.g., with alkalis or ion exchangers. Other salts can beobtained from the free bases by reaction with inorganic or organicacids, particularly those which are suitable for the formation of saltsfor therapeutical use. These salts or also other salts of the newcompound, such as, e.g., the picrate, can also serve for thepurification of the free base by converting the free base into a salt,separating this salt and again releasing the base from the salt.

The subject of the present invention is also pharmaceuticals for oral,rectal, subcutaneneous, intravenous or intramuscular application, whichcontain a combination of the active ingredients according to theinvention or their acid addition salt as the active ingredient, alongwith common vehicle and dilution agents.

The pharmacuticals of the invention are produced in the known way, witha suitable dosage, with the usual solid or liquid supports or dilutionagents and the commonly used pharmaceutical technical adjuvantscorresponding to the desired type of application. The preferredpreparations consist of a form of administration which is suitable fororal application. Such administration forms are, for example, tablets,film tablets, dragees, capsules, pills, powders, solutions orsuspensions or slow-release forms.

Of course, parenteral preparations such as injection solutions are alsoconsidered. In addition, suppositories, for example, can also be namedas preparations.

Corresponding tablets can be obtained, for example, by mixing the activeingredient with known adjuvants, for example, inert dilution agents suchas dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, burstingagents such as corn starch or alginic acid, binding agents such asstarch or gelatins, slip agents such as magnesium stearate or talcand/or agents for achieving a slow-release effect, such ascarboxypolymethylene, carboxymethylcellulose, cellulose acetatephthalate or polyvinyl acetate. The tablets can also consist of severallayers.

Correspondingly, dragees can be produced by coating cores that have beenproduced analogously to the tablets with agents usually used in drageecoatings, for example, polyvinylpyrrolidone or shellac, gum arabic,talc, titanium dioxide or sugar. The dragee envelope may also consist ofseveral layers, wherein the above-mentioned adjuvants for tablets can beused.

Solutions or suspensions containing the active ingredient according tothe invention can also contain taste-improving agents such as saccharin,cyclamate or sugar, as well as, e.g., flavorings such as vanilla ororange extract. They may also contain suspension adjuvants such assodium carboxymethylcellulose or preservatives such asp-hydroxybenzoate. Capsules containing active ingredients can beproduced, for example, by mixing the active ingredient with an inertvehicle such as lactose or sorbitol and encapsulating it in gelatincapsules.

Suitable suppositories can be produced, for example, by mixing withsupport materials provided for this purpose such as neutral fats orpolyethylene glycol or their derivatives.

The use of the combination of active ingredients according to theinvention, among other things, demonstrates the following surprisingproperties:

-   -   The physician can successfully treat a far larger spectrum of        vertigo patients with the combination of active ingredients used        according to the invention than with the individual substances        (expansion of therapeutic range, broadening of effective        profile).    -   Cinnarizine as a single substance only has the indication        “Vertigo for diagnostically clarified inner ear complaints,        i.e., for peripheral vestibular complaints”.    -   Reduction of ingestion frequency    -   Simplification of the dosage plan    -   Improvement of compliance    -   It is observed surprisingly that with a dosage of the individual        components that is reduced 2.5 times in the combination of        active ingredients used according to the invention in comparison        to the corresponding therapies with the individual substances,        the effect was increased in a statistically significant manner        with a demonstrated simultaneous reduction in the incidence of        side effects.    -   Due to the application of the fixed combination in the        combination of active ingredients used according to the        invention, the synergistic, therapeutic effect can be optimally        utilized.

The following examples explain the invention.

EXAMPLES

Studies of effectiveness with the combination of active ingredients usedaccording to the invention

The 12 clinical studies listed below were conducted; all of these wererandomized and—with the exception of Experimental Study IX—wereconducted double-blind according to the principles of “Good ClinicalPractice”, i.e., according to the most recent internationaldeterminations.

Study I

This study involves a multicenter study, in which the combination ofactive ingredients used according to the invention was compared with thehighest doses of the individual components that are commonly used inmonotherapy: cinnarizine (50 mg) and dimenhydrinate (100 mg), as well aswith placebo. The study centers were 3 ENT university clinics in Hungary(Budapest, Pecs, Debrecen). In all, 246 patients, who suffered fromperipheral-vestibular, central-vestibular or the very frequentlyoccurring combined form of peripheral-central-vestibular vertigo, wereincluded in the study. As a result, the combination of activeingredients used according to the invention was demonstrated to besuperior in a statistically highly significant manner (p≦0.001) to boththe placebo as well as to the other therapies of highly dosed individualcomponents

Study II

Patients with vertigo as a consequence of a diagnostically certainvertebro-basilar insufficiency were included in this placebo-controlledstudy at the ENT Clinic of the Medical Academy of Magdeburg. Thecombination of active ingredients used according to the invention wasdemonstrated to be statistically significantly superior to bothbetahistine (p≦0.01) as well as to placebo (p≦0.001).

Study III

Fifty patients with vertigo as a consequence of a vestibular neuropathywere included in this study at the Ear, Nose and Throat Clinic of theUniversity of Rostock. Here, the combination of active ingredients usedaccording to the invention was compared with the individual activeingredients cinnarizine (20 mg) and dimenhydrinate (40 mg)—i.e., withthe same dosage as is present in the combination of active ingredientsused according to the invention. As a result, the combination of activeingredients used according to the invention was shown to bestatistically significantly superior to both individual components(p≦0.01).

Study IV

The combination of active ingredients used according to the inventionwas also compared with the individual components in “originalconcentration” (20 mg of cinnarizine or 40 mg of dimenhydrinate) inStudy IV (3 centers: ENT Clinic of the University of Brünn, SofiaUniversity Neurological Clinic, ENT Clinic of Pilsen). Patients whosuffered from either central-vestibular, peripheral-vestibular, orcombined peripheral-central-vestibular vertigo were included. Thecombination of active ingredients used according to the invention wasshown to be statistically significantly superior to the individualcomponents (p≦0.01) in this study also.

Study V

This 2-center study was conducted at the ENT clinics of the MedicalAcademy of Dresden and the Martin Luther University of Halle. Includedwere patients who suffered from peripheral, central, or combinedperipheral-central vertigo. Comparative substances were the individualactive ingredients at high dosage: cinnarizine (50 mg) anddimenhydrinate (100 mg). The combination of active ingredients usedaccording to the invention was shown to be statistically highlysignificantly superior to the individual substances (p≦0.001).

Study VI

Study VI was conducted in the ENT Clinic, Pilsen. Included were patientswith diagnostically certain inner ear vertigo. The comparative substancein this case was betahistine. As a result, a highly significant(p≦0.001) statistical superiority of the combination of activeingredients used according to the invention was shown when compared withthe betahistine which is the standard treatment substance for thisindication.

Study VII

This study was conducted in 3 study centers (ENT Clinics in Prague,Pilsen, Budweis). Here, the combination of active ingredients usedaccording to the invention was tested against betahistine in patientswith acute vertigo complaints. The combination of active ingredientsused according to the invention was demonstrated to be statisticallysignificantly superior to the betahistine (p≦0.05) in this study also.

Study VIII

The effect of the combination of active ingredients used according tothe invention in comparison to betahistine was examined in study VIII inthe ENT Clinic of the University of Olomouc in patients withdiagnostically certain Meniere's disease. As a result, no statisticallysignificant difference was shown between the combination of activeingredients used according to the invention and the betahistine ofstandard application in Meniere's disease.

Studies IX, X

Finally, 2 experimental studies were conducted with the combination ofactive ingredients used according to the invention against placebo orthe combination of active ingredients used according to the inventionagainst betahistine by the Aerospace Medicine Group of JohannesGutenberg University in Mainz. Here, vertigo due to rotation withsimultaneous execution of head movements was induced in healthy,volunteer subjects by means of an eccentric rotating chair—as also findsuse in equilibrium training of astronauts, and the effect of thecombination of active ingredients used according to the invention wascompared with that of the placebo or with that of betahistine. In bothstudies, the effect of the combination of active ingredients usedaccording to the invention was statistically significantly superior tothe placebo (p≦0.01) or betahistine (p≦0.001) with respect to the numberof tolerated head movements.

Studies XI, XII

Further, two studies were conducted for the determination of theinfluence of the combination of active ingredients used according to theinvention on vigilance (ENT Clinic of the University of Würzburg;Institute for Brain Research, Bulgarian Academy of Sciences, Sofia). Inboth studies, the combination of active ingredients used according tothe invention showed no statistically significant difference onvigilance both when compared to betahistine as well as when compared toplacebo.

1. Use of cinnarizine and dimenhydrinate or their physiologicallycompatible salts in combination for the treatment of vertigo of anygenesis.
 2. Use of cinnarizine and dimenhydrinate or theirphysiologically compatible salts in combination for the production ofpharmaceuticals for the treatment of vertigo of any genesis.
 3. Use ofcinnarizine and dimenhydrinate or their physiologically compatible saltsin combination along with pharmaceutically compatible adjuvants and/oradditives for the production of pharmaceuticals for the treatment ofvertigo of any genesis.